Obesity promotes the progression of atherosclerosis by inducing multiple cardiovascular and metabolic derangements such as diabetes, hypertension, and dyslipidemia, all of which have high atherogenic potential. Adipose tissue has been considered an important endocrine organ that secretes many biologically active substances, collectively known as adipocytokines (1). Two major adipocytokines, leptin and adiponectin, are thought to play important roles in the regulation of cardiovascular and metabolic homeostasis. Leptin acts directly on the hypothalamus, thereby regulating food intake and energy expenditure (2). Plasma leptin concentrations are significantly elevated in obese subjects in proportion to the degree of adiposity (3), suggesting that hyperleptinemia may play a role in the pathogenesis of obesity-related complications. On the other hand, adiponectin increases tissue fat oxidation, leading to reduced levels of fatty acids and tissue triglyceride content, thus increasing insulin sensitivity (4). Paradoxically, plasma adiponectin concentrations are decreased in obese subjects (5), suggesting that hypoadiponectinemia is involved in the pathophysiology of obesity. Two recent studies have demonstrated that vascular remodeling and neointimal formation are markedly attenuated in leptin-deficient ob/ob mice and db/db mice with leptin receptor mutation (6,7), suggesting that leptin may accelerate the development of vascular injury. Conversely, studies with adiponectin-deficient mice have revealed that adiponectin plays a protective role in the development of atherosclerosis (8,9). In obese type 2 diabetic patients who are susceptible to atherosclerosis, plasma concentrations of leptin are increased, whereas those of adiponectin are decreased. We, therefore, hypothesize that the leptin-to-adiponectin ratio serves as an atherogenic index superior to leptin or adiponectin alone. This study was designed to assess the potential of the leptin-to-adiponectin ratio as a biomarker for atherosclerosis in obese type 2 diabetic patients.

A total of 158 Japanese type 2 diabetic patients (69 men and 89 women, mean age 59.8 years) were recruited in our outpatient clinics from April 2003 to May 2004 (Table 1). The study protocol was approved by the ethics committee on human research in Kyoto Medical Center, and all participants gave written informed consent. The patients had stable and relatively high blood glucose and HbA1c levels (7.0% ≤ HbA1c ≤ 9.0%). They were classified by BMI (nonobese BMI <25.0 and obese BMI ≥25.0 kg/m2, according to the criteria of the Japan Society for the Study of Obesity) (10); 98 and 60 were defined as nonobese and obese subjects, respectively. There were 39 men and 59 women in the nonobese group and 30 men and 30 women in the obese group. None were receiving insulin, metformin, or thiazolidinediones. Fifty-one nonobese and 25 obese subjects had been treated with sulfonylureas, whereas 47 and 35, respectively, had only been treated with diet.

Fasting plasma glucose, HbA1c, total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels were measured according to standard procedures. Plasma insulin concentration was measured by enzyme immunoassay using a commercially available kit (Tosoh, Tokyo, Japan). Insulin resistance index was assessed by homeostasis model assessment (11). Plasma concentrations of adiponectin and leptin were determined using the respective radioimmunoassay kits (Linco Research, St. Charles, MO). Systolic and diastolic blood pressures were measured twice with an automatic electronic sphygmomanometer (BP-103i II; Nippon Colin, Komaki, Japan). Pulse wave velocity (PWV) (12) was determined by an automated multiple pulse wave measurement (ABI-form model: BP-203RPE; Nippon Colin). In this study, PWV was calculated as the mean of the left and right brachial-ankle PWVs, as previously described (13).

Statistical analysis

All statistical analyses were performed using the StatView program version 5.0 for Windows (SAS Institute, Cary, NC). Data are presented as means ± SE, and P < 0.05 was considered statistically significant. Differences among the nonobese and obese subjects were assessed by a two-tailed Student’s t test. Significance of correlations for leptin, adiponectin, or leptin-to-adiponectin ratio with PWV was assessed by Spearman’s rank correlation analysis.

There were significant differences in BMI, plasma insulin concentration, and the homeostasis model assessment of insulin resistance between the nonobese and obese subjects (P < 0.0001), with no significant differences in systolic blood pressure, diastolic blood pressure, fasting plasma glucose, HbA1c, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. In all of the study subjects, leptin, adiponectin, and leptin-to-adiponectin ratio showed no significant correlation with PWV (leptin: ρ = −0.046 and P = 0.5676, adiponectin: ρ = 0.094 and P = 0.241, leptin-to-adiponectin ratio: ρ = −0.066 and P = 0.4086). In the lean subjects (BMI <25 kg/m2, n = 98), when divided into men and women, there were no significant correlations of leptin, adiponectin, and leptin-to-adiponectin ratio with PWV (leptin: ρ = 0.062 and P = 0.5399, adiponectin: ρ = 0.112 and P = 0.2715, leptin-to-adiponectin ratio: ρ = −0.022 and P = 0.8297). However, in the obese subjects (BMI ≥25 kg/m2, n = 60), leptin-to-adiponectin ratio was positively correlated with PWV (ρ = 0.308 and P = 0.0182), whereas leptin or adiponectin alone had no correlation (leptin: ρ = 0.255 and P = 0.0505, adiponectin: ρ = −0.130 and P = 0.3188). In the male (n = 30) and female (n = 30) patients in the obese group, leptin-to-adiponectin ratios were positively correlated with PWV (male patients: ρ = 0.378 and P = 0.0420, female patients: ρ = 0.390 and P = 0.0356), whereas leptin or adiponectin alone had no correlation in the male and female patients.

This study represents the first demonstration that in obese type 2 diabetic patients, leptin-to-adiponectin ratio is more strongly correlated with PWV than leptin or adiponectin alone. Since atherosclerosis at necropsy correlates closely with arterial stiffness assessed noninvasively in human and animal studies (12), the data of this study suggest that leptin-to-adiponectin ratio may serve as a potential atherogenic index in obese type 2 diabetic patients. With no significant correlation between leptin-to-adiponectin ratio and PWV in the nonobese subjects, we speculate that the vascular injury seen in these nonobese subjects may be related more strongly with other mechanisms than dysregulated production of adipocytokines. Evidence has suggested that leptin and adiponectin, both of which occur in the adipose tissue, act directly on vascular cells as proatherogenic and antiatherogenic factors, respectively (14,15), implying that they are important mediators linking adiposity and atherosclerosis in the adipovascular axis (9). Collectively, these observations suggest that the leptin-to-adiponectin ratio may serve as a potential atherogenic index in obese type 2 diabetic patients.

Table 1—

Baseline characteristics of the study subjects and Spearman’s rank correlation

VariablesNonobese (n = 98)
Obese (n = 60)
P values
MenWomenMenWomenMenWomen
n 39 59 30 30   
Age (years) 61.7 ± 1.41 60.9 ± 1.04 58.0 ± 2.38 57.7 ± 2.35 NS NS 
BMI (kg/m2) 22.4 ± 0.27 21.3 ± 0.29 26.6 ± 0.26 27.4 ± 0.35 <0.0001 <0.0001 
PWV (cm/s) 1667 ± 40 1700 ± 34 1628 ± 37 1634 ± 42 NS NS 
Leptin (ng/ml) 3.70 ± 0.25 5.83 ± 0.33 8.90 ± 0.35 11.9 ± 0.59 <0.0001 <0.0001 
Adiponectin (mg/ml) 4.84 ± 0.25 8.25 ± 0.28 3.44 ± 0.16 5.09 ± 0.30 0.0003 <0.0001 
Leptin/adiponectin 0.85 ± 0.08 0.79 ± 0.06 2.81 ± 0.17 2.59 ± 0.20 <0.0001 <0.0001 
Spearman’s rank correlation (P values)       
    Leptin vs. PWV −0.060 (NS) 0.053 (NS) 0.281 (NS) 0.315 (NS)   
    Adiponectin vs. PWV 0.079 (NS) 0.090 (NS) −0.309 (NS) −0.122 (NS)   
    Leptin/adiponectin vs. PWV −0.061 (NS) 0.013 (NS) 0.378 (P = 0.0420) 0.390 (P = 0.0356)   
VariablesNonobese (n = 98)
Obese (n = 60)
P values
MenWomenMenWomenMenWomen
n 39 59 30 30   
Age (years) 61.7 ± 1.41 60.9 ± 1.04 58.0 ± 2.38 57.7 ± 2.35 NS NS 
BMI (kg/m2) 22.4 ± 0.27 21.3 ± 0.29 26.6 ± 0.26 27.4 ± 0.35 <0.0001 <0.0001 
PWV (cm/s) 1667 ± 40 1700 ± 34 1628 ± 37 1634 ± 42 NS NS 
Leptin (ng/ml) 3.70 ± 0.25 5.83 ± 0.33 8.90 ± 0.35 11.9 ± 0.59 <0.0001 <0.0001 
Adiponectin (mg/ml) 4.84 ± 0.25 8.25 ± 0.28 3.44 ± 0.16 5.09 ± 0.30 0.0003 <0.0001 
Leptin/adiponectin 0.85 ± 0.08 0.79 ± 0.06 2.81 ± 0.17 2.59 ± 0.20 <0.0001 <0.0001 
Spearman’s rank correlation (P values)       
    Leptin vs. PWV −0.060 (NS) 0.053 (NS) 0.281 (NS) 0.315 (NS)   
    Adiponectin vs. PWV 0.079 (NS) 0.090 (NS) −0.309 (NS) −0.122 (NS)   
    Leptin/adiponectin vs. PWV −0.061 (NS) 0.013 (NS) 0.378 (P = 0.0420) 0.390 (P = 0.0356)   

Data are means ± SE. NS, not significant. Two-tailed Student’s t test was used.

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This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan; by research grants from the Smoking Research Foundation, the Fujisawa Foundation, the Ichiro Kanehara Foundation, the ONO Medical Foundation, AstraZeneca Research (2003), the Mitsui Sumitomo Insurance Welfare Foundation, the Takeda Medical Research Foundation, and the Takeda Science Foundation (to Y.O.); and by Research Grant 13-C5 for Cardiovascular Disease from the Ministry of Health, Labor and Welfare (to N.S.).

We thank Naoki Akamatsu for suggestions regarding statistical analysis.

1.
Matsuzawa Y, Funahashi T, Nakamura T: Molecular mechanism of metabolic syndrome X: contribution of adipocytokines, adipocyte-derived bioactive substances.
Ann N Y Acad Sci
 
892
:
146
–154,
1999
2.
Friedman JM, Halaas JL: Leptin and the regulation of body weight in mammals.
Nature
 
395
:
763
–770,
1998
3.
Considine RV, Subha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF: Serum immunoreactive-leptin concentrations in normal-weight and obese humans.
N Engl J Med
 
334
:
292
–295,
1996
4.
Matsuzawa Y, Funahashi T, Kihara S, Shimomura I: Adiponectin and metabolic syndrome.
Arterioscler Thromb Vasc Biol
 
24
:
29
–33,
2004
5.
Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y: Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.
Biochem Biophys Res Commun
 
257
:
79
–83,
1999
6.
Stephenson K, Tunstead J, Tsai A, Gordon R, Henderson S, Dansky HM: Neointimal formation after endovascular arterial injury is markedly attenuated in db/db mice.
Arterioscler Thromb Vasc Biol
 
23
:
2027
–2033,
2004
7.
Schäfer K, Halle M, Goeschen C, Dellas C, Pynn M, Loskutoff DJ, Konstantinides S: Leptin promotes vascular remodeling and neointimal growth in mice.
Arterioscler Thromb Vasc Biol
 
24
:
112
–117,
2004
8.
Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, Eto K, Yamashita T, Kamon J, Satoh H, Yano W, Frougel P, Nagai R, Kimura S, Kadowaki T, Noda T: Disruption of adiponectin causes insulin resistance and neointimal formation.
J Biol Chem
 
277
:
25863
–25866,
2002
9.
Matsuda M, Shimomura I, Sata M, Arita Y, Nishida M, Maeda N, Kumada M, Okamoto Y, Nagaretani H, Nishizawa H, Kishida K, Komuro R, Ouchi N, Kihara S, Nagai R, Funahashi T, Matsuzawa Y: Role of adiponectin in preventing vascular stenosis: the missing link of adipo-vascular axis.
J Biol Chem
 
277
:
37487
–37491,
2002
10.
The Examination Committee of Criteria for “Obesity Disease” in Japan: Japan Society for the Study of Obesity: new criteria for “obesity disease” in Japan.
Circ J
 
66
:
987
–992,
2002
11.
Haffner SM, Kennedy E, Gonzalez C, Stern MP, Miettinen H: A prospective analysis of the HOMA model: the Mexico City Diabetes Study.
Diabetes Care
 
19
:
1138
–1141,
1996
12.
Lehmann ED: Clinical value of aortic pulse-wave velocity measurement.
Lancet
 
354
:
528
–529,
1999
13.
Satoh N, Ogawa Y, Usui T, Tagami T, Kohno S, Uesugi H, Sugiyama H, Sugawara A, Yamada K, Shimatsu A, Kuzuya H, Nakao K: Antiatherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect.
Diabetes Care
 
26
:
2493
–2499,
2003
14.
Yamagishi SI, Edelstein D, Du XL, Kaneda Y, Guzman M, Brownlee M: Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A.
J Biol Chem
 
276
:
25096
–25100,
2001
15.
Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y: Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin.
Circulation
 
100
:
2473
–2476,
1999

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

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2004